Bone is the structural material of the body's framework and serves to maintain the necessary bone mass and structure. Bone contains calcium (Ca2+) and plays an important role in maintaining the calcium level in the blood. To this end, the growth of bone is a metabolic balance between the activity of osteoblasts and osteoclasts in the bone remodelling cycle.
When the balance between bone absorption and bone formation is disrupted, the amount of bone tissue replaced by osteoblasts fails to match that absorbed by osteoclasts, thus leading to osteoporosis, a common condition to cause loss of bone density or bone mass. This disease is frequently occurring in middle-aged or elderly women.
To date, the established strategy has been to produce drugs capable of preventing bone loss by inhibiting osteoclastic bone absorption. Attempts to develop alternative therapies, such as LTB-4 receptor antagonist, have been made but their development towards effective anti-osteoporotic agent has been unsuccessful due to insufficient inhibition on osteoclastic bone absorption. Therefore, there is an urgent need for new osteoporosis therapies aimed at suppressing osteoclastic bone absorption.
4-[(4-thiazolyl)-phenoxy]alkoxy-benzamidine derivative, together with its process for preparation, has been already known as leukotriene-B4 receptor antagonist (Lee Sung-eun, Synthesis and Biological Activity of Natural Products and Designed New Hybrid Compounds for the Treatment of LTB4 Related Disease, Ph.D thesis, Graduate School of Pusan Univ., August 1999).
The natural product LTB-4 is one of arachidonate metabolites formed via 5-lipoxygenase pathway [Ford-Hutchinson, A. W. et al., Nature (London), 286, 264-265, 1980].
The recent studies have focused on the influence of arachidonate metabolites on the bone tissue metabolism.
5-lipoxygenase metabolites produced from osteoblasts are found to stimulate bone absorption (Meghji, S. et. al., Calcif. Tiss. Int. 36, 139-149, 1988); the interstitial cells C433 obtained from a giant cell tumor is involved in producing 5-lipoxygenase metabolites to increase the counts and activity of osteoblasts (Mundy, G. R., J. Bio. Chem. 268, 10087-10094, 1993); the bone absorption function may be stimulated with the addition of synthetic LTB-4 during the cultivation process of bone tissue (Bonewald, L. F., J Bone Miner. Res. 11, 521-529, 1996); and Both in vitro and in vivo studies have demonstrated that LTB-4 induces the bone absorption via production of osteoclasts (Bonewald, L. F., J. Bone Miner. Res. 11, 1619-1627, 1996).
Currently, many studies have been under way with the conception that some compound showing an antagonistic action against LTB-4 receptor may affect the embolic diseases of bone tissue.
The inventors have conducted intensive studies to identify a number of diverse-structure compounds useful as effective LTB-4 receptor antagonists, aimed at suppressing osteoclastic bone absorption or stimulating osteoblastic bone formation. In consequence it has been identified that 3-amino-1,2-benzoisoxazole derivative represented by the following formula 2 is effective in the prevention and treatment of osteoporosis, while exerting antagonistic action against LTB-4 receptor. The inventors filed a patent application of such compound dated Feb. 4, 1998 (KR 98-3138).

Wherein, n is an integer of 3˜5.
In an effort to identify alternative osteoporosis therapies, the inventors have tested the inhibitory action of 4-[(4-thiazolyl)-phenoxy]alkoxy-benzamidine derivatives as LTB-4 receptor antagonist; among these derivatives, such compound as 4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}-benzamidine or N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}-benzamidine is found to be significantly effective in preventing bone loss by inhibiting osteoclastic bone absorption. Thus, the present invention has been finally completed.